Tipifarnib and Combination Chemotherapy in Treating Patients With Stage II or Stage III Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00470301
• Collaborator: (none)
• Enrollment: 60
• Locations: 7
• Arm: 1
• Duration (Months): 77
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Tipifarnib may stop the growth of breast cancer by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as paclitaxel, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving tipifarnib together with combination chemotherapy may kill more tumor cells. This phase I/II trial is studying the side effects and best dose of tipifarnib when given together with combination chemotherapy and to see how well they work in treating patients with stage II or stage III breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Male Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer	Drug: tipifarnib; Drug: paclitaxel; Drug: doxorubicin; Drug: cyclophosphamide	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the recommended phase II dose of tipifarnib when given together with paclitaxel in patients with stage IIB-IIIC breast cancer. (Phase I) II. To determine the pathologic complete remission rate (including breast and breast plus axillary nodes) in patients treated with sequential paclitaxel and tipifarnib followed by dose-dense doxorubicin hydrochloride, cyclophosphamide, and tipifarnib. (Phase II) III. To determine the feasibility and safety of this regimen in these patients. (Phase I and II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of tipifarnib followed by a phase II study.

PHASE I: Paclitaxel plus tipifarnib: Patients receive paclitaxel IV over 1 hour on day 1 and oral tipifarnib twice daily on days 1-3.

Treatment repeats weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Patients with no evidence of disease progression after 12 courses proceed to AC chemotherapy plus tipifarnib. Cohorts of 3-6 patients receive escalating doses of tipifarnib until the recommended phase II dose (RTPD) is determined. The RTPD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

AC chemotherapy plus tipifarnib: Patients receive doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 30-60 minutes on day 1, oral tipifarnib twice daily on days 2-7, and pegfilgrastim subcutaneously on day 2.

Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive paclitaxel and tipifarnib at the RTPD and AC chemotherapy plus tipifarnib as in phase I. After completion of AC plus tipifarnib (in both phases), patients are re-evaluated for surgery (i.e., modified radical mastectomy, radical mastectomy, segmental mastectomy or lumpectomy with an axillary lymph node dissection).

After completion of study treatment, patients are followed every 6 months for 5 years and then annually for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I-II Study of R115777 (Tipifarnib, Zarnestra®) Plus Sequential Weekly Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide in Patients With Stage IIB-IIIC Breast Cancer
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Tipifarnib plus sequential weekly paclitaxel followed by doxorubicin plus cyclophosphamide	Drug: tipifarnib; Given orally; Other Names: R115777 Zarnestra ; Drug: paclitaxel; Given IV; Other Names: Anzatax Asotax TAX Taxol ; Drug: doxorubicin; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana

Outcome Measures

Primary Outcome Measures

1. Pathologic Complete Response Rate (pCR) [Up to 5 years]

   An increase in the breast pCR from 15% (anticipated for chemotherapy alone) to 35% would be considered promising.

2. Number of Participants Analyzed for Phase II Dose of Tipifarnib When Combined With Weekly Sequential Paclitaxel (Phase I) [1 year]

   The recommended phase II dose of tipifarnib (100 or 200 mg PO BID on days 1-3 each paclitaxel dose) in combination with paclitaxel (80 mg/m2/week x 12 consecutive weeks)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the breast; clinical stage IIB, IIIA, IIIB, or IIIC disease

• At least 1 week since prior tamoxifen or other selective estrogen receptor modulator for prevention or for other indications (e.g., osteoporosis or prior ductal carcinoma in situ)

• HER-2/neu-negative by immunohistochemistry or fluorescence in situ hybridization (FISH)

• Hormone receptor status:

• Estrogen and/or progesterone receptor-positive* [Note: *Patients enrolled on the phase I portion of the trial may have estrogen and progesterone receptor-negative disease]

• Normal organ function including:

• WBC >= 3,000/mm^3

• Absolute neutrophil count >= 1,500/mm^3

• Platelet count >= 100,000/mm^3

• Bilirubin normal

• AST and ALT =< 2.5 times upper limit of normal

• LVEF normal by echocardiogram or nuclear scan

• Creatinine normal OR Creatinine clearance >= 60 mL/min

• FEV1 >= 1 L* and DLCO >= 50%* [Note: *Only if baseline CT scan of chest shows parenchymal lung disease OR there is a history of chronic obstructive or other pulmonary disease]

• No prior chemotherapy, radiotherapy, or definitive therapeutic surgery (e.g., mastectomy, lumpectomy, or axillary dissection) for this cancer but prior sentinel lymph node biopsy for this malignancy allowed

• No prior adjuvant chemotherapy for a previous breast malignancy

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No other concurrent investigational agents

• No other concurrent anticancer agents or therapies

• ECOG performance status 0-1

• Fertile patients must use effective contraception

Exclusion criteria:

• No other invasive malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

• No history of allergic reactions attributed to compounds of similar chemical or biological composition to tipifarnib or other study drugs (e.g., imidazoles or quinolones)

• No other uncontrolled illness including, but not limited to, any of the following: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would preclude study compliance

• Not pregnant or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
2	Albert Einstein College of Medicine	Bronx	New York	United States	10461
3	Montefiore Medical Center	Bronx	New York	United States	10467-2490
4	Mount Sinai Medical Center	New York	New York	United States	10029
5	Columbia University Medical Center	New York	New York	United States	10032
6	Weill Medical College of Cornell University	New York	New York	United States	10065
7	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Dawn Hershman, Montefiore Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00470301
• Other Study ID Numbers: NCI-2009-00239; NCI-2009-00239; 06-12-487; 7868; P30CA013330; N01CM62202; N01CM62204
• First Posted: May 7, 2007
• Last Update Posted: Feb 16, 2021
• Last Verified: Jan 1, 2021

• Additional relevant MeSH terms: Breast Neoplasms; Breast Neoplasms, Male; Paclitaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Tipifarnib

Study Results

Participant Flow

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description tipifarnib: Given orally paclitaxel: Given IV doxorubicin hydrochloride: Given IV cyclophosphamide: Given IV pegfilgrastim: Given SC conventional surgery: surgical procedures performed on patients axillary lymph node dissection: correlative study
Period Title: Overall Study
STARTED	60
COMPLETED	55
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description tipifarnib: Given orally paclitaxel: Given IV doxorubicin hydrochloride: Given IV cyclophosphamide: Given IV pegfilgrastim: Given SC conventional surgery: surgical procedures performed on patients axillary lymph node dissection: correlative study
Overall Participants	60
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	60 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	60 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	60 100%

Outcome Measures

1. Primary Outcome

Title	Pathologic Complete Response Rate (pCR)
Description	An increase in the breast pCR from 15% (anticipated for chemotherapy alone) to 35% would be considered promising.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description tipifarnib: Given orally paclitaxel: Given IV doxorubicin hydrochloride: Given IV cyclophosphamide: Given IV pegfilgrastim: Given SC conventional surgery: surgical procedures performed on patients axillary lymph node dissection: correlative study
Measure Participants	55
Number (95% Confidence Interval) [participants]	33 55%

2. Primary Outcome

Title	Number of Participants Analyzed for Phase II Dose of Tipifarnib When Combined With Weekly Sequential Paclitaxel (Phase I)
Description	The recommended phase II dose of tipifarnib (100 or 200 mg PO BID on days 1-3 each paclitaxel dose) in combination with paclitaxel (80 mg/m2/week x 12 consecutive weeks)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Total participants analyzed is 6. 3 received 100 mg PO BID tipifarnib and 3 received 200 mg PO BID tipifarnib.

Arm/Group Title	Arm I
Arm/Group Description	Tipifarnib plus sequential weekly paclitaxel followed by doxorubicin plus cyclophosphamide tipifarnib: Given orally paclitaxel: Given IV doxorubicin: Given IV cyclophosphamide: Given IV
Measure Participants	6
Number of participants with DLT (100 mg PO BID tipifarnib)	0 0%
Number of participants with DLT (200 mg PO BID tifiparnib)	0 0%

Adverse Events

Arm/Group Title	Arm I
Arm/Group Description	See Detailed Description tipifarnib: Given orally paclitaxel: Given IV doxorubicin hydrochloride: Given IV cyclophosphamide: Given IV pegfilgrastim: Given SC conventional surgery: surgical procedures performed on patients axillary lymph node dissection: correlative study
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	13/60 (21.7%)
Blood and lymphatic system disorders
Neutropenia	13/60 (21.7%)
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	28/60 (46.7%)
General disorders
Fatigue	28/60 (46.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.